Ovarian follicular growth and atresia: The relationship between cell proliferation and survival1,2

Abstract

Growth factors and steroids play an important role in the regulation of ovarian follicular development. In cattle, two of the earliest detectable differences between the healthy dominant follicle selected for development to the ovulatory stage and subordinate follicles destined to undergo atresia are the greater availability of IGF and the greater capacity to produce estradiol in the dominant follicle. We have shown that IGF-I and estradiol stimulate the proliferation of bovine granulosa cells in vitro and promote granulosa cell survival by increasing resistance to apoptosis. Furthermore, the ability of IGF-I and estradiol to increase resistance to apoptosis is tied to their ability to promote progression through the cell cycle. Blocking the cell cycle at the transition between the first gap phase and the DNA synthesis phase using a specific inhibitor prevented the protective effects of IGF-I and estradiol against apoptosis. Further experiments showed that the protective effect of IGF-I against apoptosis is mediated by the stimulation of phosphatidylinositol 3-kinase and its downstream target, protein kinase B/Akt. Constitutive activation of Akt by the infection of granulosa cells with a recombinant Akt adenovirus protected against apoptosis, and this effect also depended on cell cycle progression. These experiments show that the protective effect of estradiol and IGF-I against apoptosis depends on unperturbed progression through the cell cycle. Once follicles have developed to the preovulatory stage, the LH surge induces terminal differentiation of granulosa cells and withdrawal from the cell cycle. Bovine granulosa cells withdraw from the cell cycle by 12 h after the LH surge and become resistant to apoptosis, even in the absence of growth factors. Treatment with a progesterone receptor antagonist in vitro caused reentry of granulosa cells into the cell cycle and susceptibility to apoptosis, suggesting that induction of progesterone receptor expression by the LH surge is required for cell cycle withdrawal and resistance to apoptosis. In summary, the susceptibility of granulosa cells to apoptosis depends on the cell cycle. Proliferating granulosa cells in growing follicles depend on growth factors for survival, whereas cells that have terminally differentiated in response to the LH surge are resistant to apoptosis and relatively independent of growth factors for survival.

Role of transforming growth factor-β1 in gene expression and activity of estradiol and progesterone-generating enzymes in FSH-stimulated bovine granulosa cells

“…The moderate increase in total cell protein observed in the presence of FSH could indicate that FSH stimulated proliferation or, alternatively, that FSH prevented apoptosis and increased cell survival. FSH and E 2 are known to act as survival factors to induce granulosa cell proliferation and prevent apoptosis (Gutierrez et al 1997, Yang & Rajamahendran 2000, Jiang et al 2003, Quirk et al 2004. In the present study, TGFB1 caused visible differences in the morphology of granulosa cell clumps, which appeared smaller and more spherical than those in FSH-treated controls.…”

“…Similarly, TGFB1 alone had no effect on DNA synthesis in cultured bovine granulosa cells (Lerner et al 1995). Therefore, the effects of TGFB1 on granulosa cells could be due to inhibition of the cellsurviving activity of FSH and/or mediated through a loss of E 2 -stimulated cell survival (Yang & Rajamahendran 2000, Quirk et al 2004. Ongoing experiments in our laboratory will test this hypothesis, by investigating the effects of TGFB1 on proliferation and apoptosis of bovine granulosa cells cultured with or without FSH.…”

JY-1 , an oocyte-specific gene, regulates granulosa cell function and early embryonic development in cattle

“…Biological actions of JY-1 on bovine granulosa cells do not mimic the reported effects of the well known oocyte-specific growth factors GDF9 and BMP15 on bovine granulosa cell function (34,35). In vivo, the preovulatory gonadotropin (luteinizing hormone) surge results in decreased estradiol and increased progesterone levels in the follicular fluid of bovine preovulatory follicles (36), and preovulatory granulosa cells exit from the cell cycle and are transformed into nondividing terminally differentiated luteal cells capable of producing high levels of progesterone (37,38). In our culture studies, the increase in progesterone was accompanied by a suppression of the FSH-stimulated increase in granulosa cell numbers and estradiol production, mimicking the in vivo preovulatory follicular environment.…”

HDC gene polymorphisms are associated with age at natural menopause in Caucasian women

“…Different kinds of hormone, growth factors, and cytokine are involved in these processes [29][30][31][32]. Bodis J's study found that histamine could directly stimulate the steroid production of ovarial granulosa cells [33].…”